Coccidioidomycosis is an important infection in the Southwestern United States that is responsible for considerable morbidity and mortality. In one California county alone, Coccidioides immitis has caused up to 3,000 symptomatic infections/year. The incidence of disseminated (extra- pulmonary) infection is high in pregnancy, the immunosuppressed, and some ethnic groups (African-Americans and Filipinos, particularly). We know that solid immunity does occur because second infections are extraordinarily rare; T--cell mediated immunity, not humoral immunity is the protective response. The overall goal of this program attempts to identify C. immitis antigen(s) which are effective as a vaccine for experimental murine coccidioidomycosis. All five projects in this program directly contribute to this goal. We propose to use a molecular approach in identifying C. immitis spherule proteins which 1) elicit T-lymphocyte proliferative responses in mice immune to C. immitis, 2) stimulate C. immitis-specific T-cell lines, 3) immunize mice to make T-lymphocyte proliferative responses to C. immitis, and 4) stimulate proliferative T- cell responses in people immune to C. immitis. Some T-cell reactive proteins have already been identified and cloned; others will be identified by a novel approach: using "naked DNA" vectors carrying C. immitis cDNA to immunize mice and determine whether they develop T-lymphocyte responses to C. immitis. The critical t-cell types and cytokine responses in murine coccidioidomycosis will be identified an the candidate antigens tested for ability to elicit these responses. The genes coding for t-cell reactive proteins will be sequenced in a genetically defined group of C. immitis isolates to determine the degree of conservation o the antigens. With all this information in hand, the most promising antigens will be selected for immunoprotection studies, which will be done in mice. This information should lay the groundwork needed for development of a human coccidioidomycosis vaccine.